Targeted Delivery of PD-L1-Derived Phosphorylation-Mimicking Peptides by Engineered Biomimetic Nanovesicles to Enhance Osteosarcoma Treatment.

Abstract

Osteosarcoma is a rare malignant bone-originating tumor that usually occurs in young people. Programmed cell death 1 ligand 1 (PD-L1), an immune checkpoint protein, is highly expressed in osteosarcoma tissues. Several recent studies have indicated that the tumor-related role of PD-L1 in tumors, especially non-plasma membrane (NPM)-localized PD-L1, is not limited to immune regulation in osteosarcoma. Here, mass spectrometry analysis is combined with RNA-seq examination to identify the intracellular binding partners of PD-L1 and elucidate the underlying mechanism of its action. It is found that the NPM-localized PD-L1 interacted with Insulin-like growth factor binding protein-3 (IGFBP3) to promote osteosarcoma tumor growth by activating mTOR signaling. This interaction is enforced after phosphoglyceratekinase1 (PGK1)-mediated PD-L1 phosphorylation. Based on these findings, a phosphorylation-mimicking peptide is designed from PD-L1 and it is encapsulated with a Cyclic RGD (cRGD)-modified red blood cell membrane (RBCM) vesicle (Peptide@cRGD-M). The Peptide@cRGD-M precisely delivers the PD-L1-derived phosphorylation-mimicking peptide into osteosarcoma lesions and significantly promotes its therapeutic effect on the tumor. Therefore, this investigation not only highlights the function of NPM-localized PD-L1, but also uses an engineering approach to synthesize a small molecular peptide capable of inhibiting osteosarcoma growth.

• Authors: Wei Wu, Haoyu Guo, Doudou Jing, Zhenhao Zhang, Zhicai Zhang, Feifei Pu, Wenbo Yang, Xin Jin, Xin Huang, Zengwu Shao
• Journal: Advanced healthcare materials (Adv Healthc Mater) Vol. 11 Issue 23 Pg. e2200955 (12 2022) ISSN: 2192-2659 [Electronic] Germany
• PMID: 36123781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

Chemical References

• B7-H1 Antigen
• Peptides

Topics

• Humans
• B7-H1 Antigen
• Biomimetics
• Osteosarcoma (drug therapy)
• Peptides